Affinage

Showing FGF13 — FHF2 is a alias.

FGF13

Fibroblast growth factor 13 · UniProt Q92913

Length
245 aa
Mass
27.6 kDa
Annotated
2026-06-09
68 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FGF13 (FHF2) is a nonsecreted, intracellular protein that functions as an auxiliary subunit of voltage-gated sodium channels (VGSCs) and as a multifunctional regulator of channel trafficking, microtubule stability, and gene expression across cardiac, sensory, and central neurons (PMID:27044086, PMID:41289026). It binds directly to the cytoplasmic C-terminus of Nav1.5, Nav1.6, and Nav1.7, and through splice isoform-specific effects tunes current density, fast and slow inactivation, steady-state availability, and recovery from inactivation (PMID:27246624, PMID:31223136, PMID:27999940). In heart, FGF13 sustains sodium current and conduction—its loss accelerates channel inactivation, reduces peak current, prolongs QRS, and produces temperature-sensitive conduction failure (PMID:28119060, PMID:27701382), with conduction further compromised by interdependence between reduced Nav availability, calcium current, and gap-junctional coupling (PMID:32962518). A separation-of-function mechanism shows that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc rather than solely through direct channel binding (PMID:40794434), and it directs Cx43 gap junction trafficking through microtubule-dependent, VGSC-independent routes (PMID:41200819). In sensory neurons, FGF13 binds Nav1.7 in a heat- and histamine-facilitated manner to sustain nociceptive and pruriceptive firing, and disruption or stabilization of this interaction bidirectionally controls pain and itch behavior (PMID:28162808, PMID:33172979, PMID:40662354). Through a conserved tubulin-binding domain FGF13 stabilizes microtubules to control trafficking of diverse cargoes including Kv4.2/4.3 channels, Cav1.2, TRPV1, and platinum transporters (PMID:28119060, PMID:38733310, PMID:38821375, PMID:34533854). Nuclear FGF13 isoforms additionally regulate transcriptional programs—repressing ribosomal RNA synthesis in the nucleolus (PMID:27994142), activating NF-κB via direct p65 binding in cardiac hypertrophy (PMID:33089113), and interacting with the BAF subunit ARID1B to maintain neural stem cell self-renewal (PMID:34010636). FGF13 deficiency causes hyperthermia-induced seizures via excitatory-inhibitory imbalance (PMID:26063919), with interneuron-specific loss producing sodium-channel-independent seizures through reduced K+ currents (PMID:39773461); missense variants in FHF2A cause developmental and epileptic encephalopathy (PMID:33245860), and a 5'-UTR variant impairing PTBP2-dependent translation causes neuronal migration defects and cognitive deficits (PMID:34184986).

Mechanistic history

Synthesis pass · year-by-year structured walk · 32 steps
  1. 2016 High

    Established that FGF13 directly binds VGSCs and, in concert with FGF14, polarizes sodium channel distribution within neurons—defining its role as a trafficking and localization regulator rather than only a gating modulator.

    Evidence Knockdown and interaction-abolishing mutagenesis in hippocampal neurons with immunofluorescence and electrophysiology

    PMID:27044086

    Open questions at the time
    • Mechanism by which FGF13 restricts somatodendritic localization not resolved at the molecular level
    • Did not address cardiac or sensory neuron contexts
  2. 2016 High

    Showed that distinct FGF13 splice isoforms differentially shape Nav1.5 gating, establishing isoform identity as a determinant of channel behavior.

    Evidence Heterologous HEK293 expression with isoform-specific constructs and whole-cell voltage-clamp

    PMID:27246624

    Open questions at the time
    • Heterologous system may not reflect native stoichiometry
    • Physiological relevance of FGF13S slow-inactivation effect in vivo not tested
  3. 2016 High

    Demonstrated that FGF13 loss produces temperature-sensitive cardiac conduction failure via accelerated sodium channel inactivation, linking the subunit to thermal stability of cardiac excitability.

    Evidence Fhf2 knockout mice, temperature-series patch-clamp, ECG, and computational modeling

    PMID:27701382

    Open questions at the time
    • Did not address contribution of non-VGSC mechanisms to conduction
  4. 2015 High

    Linked FGF13 to seizure susceptibility, showing heterozygous loss causes hyperthermia-induced seizures through synaptic excitatory-inhibitory imbalance.

    Evidence Fgf13 knockout mice with hippocampal mIPSC/mEPSC recordings and hyperthermia seizure induction

    PMID:26063919

    Open questions at the time
    • Cell-type origin of E/I imbalance not resolved in this study
    • Molecular mechanism connecting FGF13 to synaptic inputs unclear
  5. 2017 High

    Defined FGF13's cardiac phenotype—reduced Na+ current, inactivation shift, QRS prolongation—and revealed an unexpected role in surface localization of Kv4.2/4.3, expanding its function to K+ channel trafficking.

    Evidence Inducible cardiomyocyte-restricted Fgf13 KO mice with electrophysiology, ECG, and surface fractionation

    PMID:28119060

    Open questions at the time
    • Mechanism of Kv4 surface regulation not defined at the time
    • Whether trafficking effect is direct unaddressed
  6. 2017 High

    Established FGF13 as required for heat nociception by maintaining Nav1.7 currents and membrane localization in a heat-facilitated interaction, providing a druggable PPI target for pain.

    Evidence DRG-conditional KO mice, co-IP, patch-clamp, competitive peptide disruption, and behavioral assays

    PMID:28162808

    Open questions at the time
    • Molecular basis of heat-facilitation of the interaction not defined
    • Whether peptide effects are Nav1.7-specific in vivo not fully resolved
  7. 2017 High

    Connected FGF13 to disease-relevant channel dysregulation by showing CaMKII-driven phosphorylation of Nav1.5 disrupts FGF13 binding and downstream calmodulin recruitment, defining a pathway altered in failing hearts.

    Evidence Phosphoproteomics of native Nav1.5, phosphomimetic mutants, voltage-clamp, and co-IP

    PMID:28882890

    Open questions at the time
    • In vivo significance of the two phosphosites not tested
    • Structural basis of FGF13-calmodulin cooperativity unresolved
  8. 2016 Medium

    Identified a nuclear, growth-suppressive role for the FGF13 1A isoform in repressing rRNA transcription within a p53 feedback loop, distinguishing nuclear from channel-associated functions.

    Evidence Subcellular fractionation, rRNA transcription assays, siRNA depletion with apoptosis readout, and p53 ChIP

    PMID:27994142

    Open questions at the time
    • Direct mechanism of rRNA repression by FGF13 1A unknown
    • Single-lab finding
  9. 2016 Medium

    Resolved opposing isoform effects on Nav1.6 resurgent current, showing FHF2A and FHF2B regulate sensory excitability in antagonistic directions.

    Evidence DRG and heterologous patch-clamp with isoform-specific and chimeric constructs

    PMID:27999940

    Open questions at the time
    • Single lab
    • In vivo pain relevance of resurgent-current modulation not established
  10. 2017 High

    Revealed a VGSC-independent cardiac function: FGF13 negatively regulates caveolae abundance by controlling cavin-1 distribution, conferring protection against pressure overload.

    Evidence Cardiac Fgf13 KO mice, interactome screen/co-IP, fractionation, EM, and pressure overload model

    PMID:28461495

    Open questions at the time
    • Mechanism by which FGF13 controls cavin-1 partitioning not defined
    • Link between caveolae and protection partly correlative
  11. 2019 High

    Confirmed isoform-dependent FHF2 regulation of Nav1.7 in both native and heterologous cells, reinforcing isoform-specific control of sensory channel availability.

    Evidence Co-IP/immunohistochemistry in DRG with patch-clamp and knockdown

    PMID:31223136

    Open questions at the time
    • Structural determinants of isoform-specific effects not mapped
  12. 2020 Medium

    Identified nuclear FGF13 as a direct activator of NF-κB via p65 binding through an IκB-independent route, linking the protein to hypertrophic gene programs.

    Evidence Co-IP, confocal co-localization, gain/loss-of-function in cardiomyocytes/TAC, and NF-κB reporter

    PMID:33089113

    Open questions at the time
    • Mechanism of IκB-independent activation unclear
    • Single lab
  13. 2020 High

    Established FGF13 missense variants as a cause of developmental and epileptic encephalopathy through selective loss of Nav1.6 long-term blockade with retained pro-excitatory effects.

    Evidence Whole-exome sequencing and functional patch-clamp of mutant FHF2A co-expressed with Nav1.6

    PMID:33245860

    Open questions at the time
    • In vivo neuronal consequences of variants not modeled
    • Single lab functional characterization
  14. 2020 High

    Showed conduction failure in FHF2-deficient cardiac strands arises from combined Nav and gap-junctional deficits, integrating ionic and electrotonic determinants of propagation.

    Evidence Fhf2 KO with pharmacology, Cx43-heterozygous cross, multicellular modeling, and optical mapping

    PMID:32962518

    Open questions at the time
    • Mechanistic basis of reduced gap-junctional conductance not defined here
  15. 2020 High

    Extended FGF13/Nav1.7's sensory role to itch, showing histamine enhances the interaction in an isoform-dependent manner to drive pruriception.

    Evidence DRG-specific KO mice, co-IP, calcium imaging, competitive peptide, and behavior

    PMID:33172979

    Open questions at the time
    • Molecular basis of histamine-facilitated binding unresolved
  16. 2021 High

    Linked FGF13 to neurodevelopment by showing a 5'-UTR variant impairs PTBP2-dependent translation, reducing microtubule stabilization and causing migration and cognitive deficits.

    Evidence Patient iPSCs, translation assays, PTBP2 pulldown, knockin mice, and microtubule polymerization assays

    PMID:34184986

    Open questions at the time
    • Whether migration defect reflects loss of channel or microtubule function not fully separated
  17. 2021 Medium

    Defined a chromatin-level function: nuclear FGF13A binds the BAF subunit ARID1B to suppress neuronal differentiation genes and maintain neural stem cell self-renewal.

    Evidence Fgf13 conditional KO, co-IP, ChIP, neurogenesis assays, and RNA-seq

    PMID:34010636

    Open questions at the time
    • Direct chromatin targets and how FGF13A is recruited not fully defined
    • Single lab
  18. 2021 Medium

    Established that FGF13's tubulin-binding domain drives chemoresistance by redistributing platinum transporters, generalizing the microtubule-trafficking function to cancer pharmacology.

    Evidence Overexpression/knockdown in cancer cell lines, platinum uptake assays, fractionation, and domain-mutant rescue

    PMID:34533854

    Open questions at the time
    • In vivo relevance and clinical correlation limited
    • Single lab
  19. 2023 Medium

    Confirmed FHF2 is extensively phosphorylated in native cardiac Nav1.5 complexes and modulates late current, but individual phosphosites were not assignable to specific functions.

    Evidence Phosphoproteomics of native Nav complexes with cardiomyocyte knockdown/rescue (preprint)

    PMID:36778222

    Open questions at the time
    • Functional role of individual phosphosites inconclusive (negative result)
    • Preprint, not peer reviewed
  20. 2023 Medium

    Placed FGF13 upstream of Parkin in glomerular endothelial mitochondrial homeostasis, showing its deficiency improves mitophagy in diabetic nephropathy.

    Evidence Endothelial-specific Fgf13 and double Fgf13/Prkn KO mice with mitophagy and apoptosis assays

    PMID:36256844

    Open questions at the time
    • Direct molecular link between FGF13 and Parkin not defined
    • Single lab
  21. 2024 Medium

    Showed FGF13 microtubule stabilization impairs cardiac calcium handling in heart failure by reducing Cav1.2 surface localization and Serca2α, identified via domain-mutant rescue.

    Evidence TAC heart failure model, Fgf13 KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue

    PMID:38821375

    Open questions at the time
    • Mechanism linking microtubule stability to Serca2α expression unclear
    • Single lab
  22. 2024 Medium

    Demonstrated FGF13 selectively enhances TRPV1 (not TRPA1) function via its microtubule-stabilizing domain to drive itch behaviors.

    Evidence DRG-specific KO, calcium imaging, patch-clamp, and tubulin-binding mutant rescue with behavior

    PMID:38733310

    Open questions at the time
    • Basis of TRPV1-versus-TRPA1 selectivity unresolved
    • Single lab
  23. 2024 Medium

    Linked FGF13 microtubule function to cardiac fibrosis, showing its loss reduces fibrosis via microtubule destabilization and decreased ROCK.

    Evidence TAC model, fibroblast culture, and tubulin-binding mutant rescue of fibrosis markers

    PMID:38818580

    Open questions at the time
    • Mechanism linking microtubule disruption to ROCK downregulation unclear
    • Single lab
  24. 2025 High

    Separated FGF13's regulation of cardiac conduction from VGSC binding, showing it controls Cx43 gap junction trafficking through microtubule-dependent mechanisms.

    Evidence Cardiac Fgf13 KO, optical mapping, proximity proteomics, and VGSC-binding-incompetent mutant rescue

    PMID:41200819

    Open questions at the time
    • How FGF13 directs Cx43 to the intercalated disc mechanistically not fully resolved
  25. 2025 High

    Revealed that FGF13 regulates Nav1.5 steady-state inactivation indirectly by maintaining polarized accessible membrane cholesterol at the intercalated disc, overturning a purely direct-binding model.

    Evidence Fgf13-KO cardiomyocytes, binding-incompetent mutant rescue, cholesterol imaging, and patch-clamp

    PMID:40794434

    Open questions at the time
    • Mechanism by which FGF13 maintains cholesterol polarization not defined
  26. 2025 High

    Distinguished cell-type-specific seizure mechanisms, showing interneuron Fgf13 loss causes sodium-channel-independent seizures through reduced K+ currents.

    Evidence Interneuron- versus excitatory-neuron-specific conditional KO mice with patch-clamp and isoform rescue

    PMID:39773461

    Open questions at the time
    • Identity of the affected K+ channels not defined
    • Mechanism of K+ current regulation unclear
  27. 2025 High

    Definitively established FGF13 as nonsecreted and intracellular, constraining all proposed functions to intracellular and membrane-associated compartments.

    Evidence Conditioned-medium analysis with rigorous controls and proximity labeling proteomics

    PMID:41289026

    Open questions at the time
    • Does not address possible non-canonical release under specific stress conditions
  28. 2025 High

    Advanced FGF13/Nav1.7 as a bidirectional therapeutic target, with PPI inhibitor and stabilizer producing mirror-image analgesic and pronociceptive effects in human neurons and mice.

    Evidence Small-molecule PPI inhibitor/stabilizer, hIPSC sensory neurons, siRNA, mouse behavior, and donor DRG tissue

    PMID:40662354

    Open questions at the time
    • Selectivity of compounds for FGF13/Nav1.7 over other FHF/Nav pairs not fully defined
  29. 2025 Medium

    Identified a mitochondrial anchoring function, with FGF13 binding the outer mitochondrial membrane protein MCHT2 to retain damaged mitochondria and limit neurodegeneration.

    Evidence Co-IP, Fgf13 overexpression in PD models, and glia-neuron co-culture/mitochondria transfer assays

    PMID:40344619

    Open questions at the time
    • Direct nature and stoichiometry of FGF13-MCHT2 interaction not detailed
    • Single lab
  30. 2025 Medium

    Connected FGF13 to cardiomyocyte senescence through Cav1 promoter regulation via p38/MAPK and p65, plus PTRF-Cav1 modulation, defining a Cav1-p53-p21 aging axis.

    Evidence AAV9 overexpression, cardiac Fgf13 KO, transcriptomics, Cav1 luciferase reporter, and co-IP

    PMID:40184605

    Open questions at the time
    • Relationship between nuclear and trafficking roles in senescence unclear
    • Single lab
  31. 2026 Medium

    Identified TUBB2A as a direct FGF13 partner mediating microtubule stabilization, with FGF13 methylation reducing binding and FGF13 protecting against Alzheimer's-related deficits.

    Evidence Co-IP, methylation-specific PCR, FGF13 overexpression in an Aβ AD model, and TUBB2A knockdown epistasis

    PMID:41808420

    Open questions at the time
    • Functional consequence of FGF13 methylation in vivo not established
    • Single lab
  32. 2020 Low

    Reported FGF13 interaction with SHCBP1 promoting AKT-GSK3 signaling and proliferation in lung cancer cells.

    Evidence Co-IP, Western blotting, flow cytometry cell cycle, and proliferation assays

    PMID:33064958

    Open questions at the time
    • Single co-IP without reciprocal validation or in vivo confirmation
    • Direct versus indirect interaction not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How FGF13's distinct mechanistic modules—direct channel binding, microtubule stabilization, membrane cholesterol polarization, and nuclear transcriptional regulation—are partitioned by isoform, post-translational modification, and cell type into coherent physiological outputs remains unresolved.
  • No unified structural model integrating channel-binding and microtubule-binding domains
  • Determinants directing FGF13 isoforms to nuclear versus membrane functions undefined
  • Mechanism of cholesterol polarization at the intercalated disc unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6 GO:0008092 cytoskeletal protein binding 4 GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 3
Localization
GO:0005856 cytoskeleton 4 GO:0005886 plasma membrane 4 GO:0005634 nucleus 2 GO:0005730 nucleolus 1 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-9609507 Protein localization 4 R-HSA-397014 Muscle contraction 3 R-HSA-162582 Signal Transduction 2 R-HSA-74160 Gene expression (Transcription) 2
Partners
ARID1BCAV1PTRFRELASCN5ASCN8ASCN9ATUBB2A
Complex memberships
BAF chromatin remodeling complexNav1.5 channel complexNav1.7 channel complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 FGF13 binds directly to voltage-gated sodium channels (VGSCs) in hippocampal neurons and limits their somatodendritic surface expression, while FGF14 (a homolog) promotes axonal VGSC localization; single-point mutations in FGF13 that abrogate VGSC interaction in vitro cannot support somatodendritic restriction in neurons. Together, FGF13 and FGF14 act concertedly to polarize VGSC distribution to the axon initial segment. Knockdown in hippocampal neurons, in vitro VGSC-interaction mutagenesis, immunofluorescence localization, electrophysiology Proceedings of the National Academy of Sciences of the United States of America High 27044086
2017 FGF13 interacts with Nav1.7 in DRG neurons in a heat-facilitated manner, increases Nav1.7 sodium currents, and maintains membrane localization of Nav1.7 during noxious heat stimulation, enabling sustained action potential firing required for heat nociception. Loss of FGF13 in DRG neurons selectively abolishes heat nociception. Disruption of the FGF13/Nav1.7 interaction with a competitive peptide reduces heat-evoked action potential firing and nociceptive behavior. Conditional knockout mice, co-immunoprecipitation, patch-clamp electrophysiology, competitive peptide disruption, behavioral assays Neuron High 28162808
2016 Cardiac FGF13 directly binds to the C-terminus of NaV1.5, and different FGF13 splice variants (FGF13S, FGF13U, FGF13VY) differentially modulate NaV1.5 current density, fast inactivation (open-state and closed-state), steady-state availability, and slow inactivation. FGF13S uniquely hastens slow inactivation entry and dramatically slows recovery, causing large current reduction at high frequency stimulation. Heterologous expression in HEK293 cells, whole-cell voltage-clamp electrophysiology, isoform-specific expression constructs Channels (Austin, Tex.) High 27246624
2017 Cardiac-specific Fgf13 knockout reduces peak Na+ channel current density (~25%), causes a hyperpolarizing shift in steady-state inactivation, prolongs QRS duration, and reduces transient outward K+ current (Ito) by decreasing Kv4.2 and Kv4.3 sarcolemmal localization without altering their total protein levels. Voltage-gated Ca2+ current was not affected. Inducible cardiomyocyte-restricted Fgf13 knockout mice, patch-clamp electrophysiology, ECG recording, immunoblotting, surface fractionation Journal of molecular and cellular cardiology High 28119060
2016 Mice lacking FHF2 (FGF13) show normal cardiac rhythm at baseline but develop temperature-sensitive cardiac conduction failure at elevated temperatures. Absence of FHF2 accelerates both closed-state and open-state sodium channel inactivation, which synergizes with temperature-dependent enhancement of inactivation to severely suppress cardiac sodium currents at elevated temperatures. Fhf2 knockout mice, patch-clamp electrophysiology at multiple temperatures, ECG recording, computational modeling Nature communications High 27701382
2017 FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 (PTRF) between the sarcolemma and cytosol. In cardiac Fgf13 knockout mice, cavin 1 redistributes to the sarcolemma, stabilizes caveolin 3, increases caveolae density, and confers protection against pressure overload-induced cardiac dysfunction. The full FGF13 interactome in cardiomyocytes was found to include the complete set of cavin family caveolar coat proteins. Inducible cardiac-specific Fgf13 knockout mice, co-immunoprecipitation/interactome screen, biochemical fractionation, electron microscopy for caveolae density, cardiac pressure overload model Proceedings of the National Academy of Sciences of the United States of America High 28461495
2015 Disruption of Fgf13 in female mice (heterozygous deletion) causes hyperthermia-induced seizures and epilepsy associated with a synaptic excitatory-inhibitory imbalance: decreased inhibitory and increased excitatory synaptic inputs in hippocampal neurons. Fgf13 knockout mice, hippocampal electrophysiological recordings (miniature IPSCs and EPSCs), hyperthermia seizure induction The Journal of neuroscience : the official journal of the Society for Neuroscience High 26063919
2017 C-terminal phosphorylation of NaV1.5 at Ser1938 and Ser1989 (increased in CaMKIIδc-overexpressing failing hearts) abrogates FGF13-dependent regulation of NaV1.5 channel inactivation. FGF13 normally increases NaV1.5 channel availability and decreases late Na+ current; phosphomimetic mutations at both sites abolish these effects by reducing FGF13 binding to NaV1.5 and consequently reducing calmodulin recruitment to NaV1.5. FGF13 was shown to potentiate calmodulin binding to NaV1.5. Phosphoproteomics of purified NaV1.5 from WT and CaMKIIδc-Tg mouse ventricles, whole-cell voltage-clamp in HEK293 cells, co-immunoprecipitation The Journal of biological chemistry High 28882890
2020 FGF13 directly interacts with p65 (NF-κB subunit) via its nuclear localization sequence, co-localizes with p65 in the nucleus in cardiac hypertrophy, and activates NF-κB signaling by an IκB-independent mechanism. FGF13 deficiency inhibits NF-κB activation and overexpression alone is sufficient to activate NF-κB in cardiomyocytes. Co-immunoprecipitation, confocal co-localization, gain- and loss-of-function in cardiomyocytes and TAC mouse model, NF-κB reporter assay iScience Medium 33089113
2016 FGF13 1A isoform localizes to the nucleolus and represses ribosomal RNA transcription, attenuating protein synthesis. The FGF13 locus (encompassing FGF13 and miR-504) is transcriptionally repressed by p53, defining a negative feedback loop. In cancer cells expressing high FGF13, its depletion causes proteostasis stress, reactive oxygen species accumulation, and apoptosis. Subcellular fractionation/confocal microscopy for nucleolar localization, ribosomal RNA transcription assays, siRNA depletion with apoptosis readout, p53 chromatin immunoprecipitation Proceedings of the National Academy of Sciences of the United States of America Medium 27994142
2021 FGF13 stabilizes microtubules in developing cortical neurons. A 5'-UTR SNP (c.-32C>G) in FGF13 reduces translation of FGF13 by impairing its interaction with polypyrimidine-tract-binding protein 2 (PTBP2), which is required for FGF13 translation in cortical neurons. Reduced FGF13 causes delayed neuronal migration and cognitive deficits. Patient-derived iPSCs and HEK293 cell translation assays, RNA-binding protein pulldown (PTBP2), knockin mice carrying homologous 5'-UTR point mutation, microtubule polymerization assays eLife High 34184986
2019 FHF2 (FGF13) isoforms FHF2A and FHF2B associate with Nav1.7 in DRG neurons and regulate its current properties in an isoform-dependent manner. FHF2A causes accumulation of inactivated channels and slows recovery from inactivation, while FHF2B depolarizes activation. Effects were confirmed by FHF2 knockdown in DRG neurons. Co-immunoprecipitation/immunohistochemistry in DRG neurons, whole-cell patch-clamp in HEK293-Nav1.7 cells and DRG neurons with FHF2 knockdown Neurobiology of pain (Cambridge, Mass.) High 31223136
2016 FHF2A (FGF13A) negatively regulates Nav1.6-mediated resurgent sodium currents in DRG neurons by enhancing long-term inactivation and delaying recovery, while FHF2B positively regulates resurgent current. Chimeric FHF2A/Navβ4 constructs revealed distinct regulatory regions. FHF2A and FHF2B isoform expression is differentially regulated in a radicular pain model. Whole-cell patch-clamp in DRG neurons and heterologous cells, FHF2 isoform-specific expression/knockdown, chimeric construct analysis Pflugers Archiv : European journal of physiology Medium 27999940
2020 Missense variants in the N-terminal domain of FHF2A (FGF13 A isoform) cause loss of the ability to induce rapid-onset, long-term blockade of Nav1.6 (SCN8A) channels while retaining pro-excitatory properties, resulting in gain-of-function neuronal hyperexcitability consistent with developmental and epileptic encephalopathy. Whole-exome sequencing identifying variants, functional characterization by co-expression of mutant FHF2A with Nav1.6 in heterologous cells (whole-cell patch-clamp) American journal of human genetics High 33245860
2020 FHF2-deficient cardiomyocytes show that reduced Nav availability shifts dependence onto calcium current (ICa) to sustain electrotonic driving force and action potential propagation from cell-to-cell. Diminished gap junctional conductance (Gj) conspires with accelerated Nav inactivation in FHF2-deficient strands to prevent sufficient downstream cell charging for action potential propagation. Fhf2 knockout mice, pharmacological reduction of gCaL (verapamil) or Gj (carbenoxolone), Cx43-heterozygous backcross, multicellular linear strand computational modeling, optical mapping Circulation research High 32962518
2025 FGF13 regulates cardiac impulse propagation via a VGSC-independent mechanism by controlling microtubule-dependent trafficking and targeting of Cx43 (connexin 43) gap junctions. FGF13 ablation destabilizes microtubules, reduces MAP4 expression, perturbs Cx43 trafficking to the intercalated disc, increases Cx43 hemichannels, and depolarizes resting membrane potential. A mutant FGF13 incapable of binding VGSCs fully restores these defects, demonstrating VGSC independence. Cardiac-specific Fgf13 KO mice, optical mapping, pharmacological gap junction/hemichannel manipulation, proximity labeling proteomics, immunostaining, VGSC-binding-incompetent FGF13 mutant rescue Circulation research High 41200819
2025 FGF13 regulation of NaV1.5 steady-state inactivation (SSI) is mediated through effects on local accessible membrane cholesterol rather than through direct channel binding. A binding-incompetent FGF13 mutant (structurally guided) still completely restores WT regulation of SSI in Fgf13-KO cardiomyocytes. FGF13 maintains polarized cholesterol distribution concentrated at the intercalated disc where VGSCs localize; Fgf13-KO eliminates this cholesterol polarization and causes VGSC loss from the intercalated disc. Fgf13-KO cardiomyocytes, binding-incompetent FGF13 mutant rescue, cholesterol labeling/filipin staining, patch-clamp electrophysiology, proximity labeling proteomics The Journal of clinical investigation High 40794434
2025 Interneuron-specific deletion of Fgf13 causes perinatal mortality with extensive seizures and impaired hippocampal inhibitory/excitatory balance, while excitatory neuron-targeted deletion causes no seizures. The seizure mechanism in interneurons is sodium channel-independent; instead, Fgf13 ablation in interneurons markedly reduces K+ channel currents. Re-expression of different Fgf13 splice isoforms partially rescues interneuron excitability deficits and restores K+ current amplitude. Cell-type-specific conditional Fgf13 knockout mice (interneuron vs. excitatory neuron Cre lines), patch-clamp electrophysiology, isoform rescue experiments eLife High 39773461
2020 FGF13 is required for histamine-induced itch sensation in DRG neurons. Histamine enhances the FGF13/Nav1.7 interaction. Disruption of FGF13/Nav1.7 interaction by a membrane-permeable competitive peptide (GST-Flag-NaV1.7CT-TAT) reduces histamine-responsive DRG neurons and impairs scratching behavior. The histamine-evoked neuronal response is primarily mediated via H1R and is FGF13B isoform-dependent. DRG-specific Fgf13 KO mice, co-immunoprecipitation, calcium imaging, electrophysiology, competitive peptide disruption, behavioral assays The Journal of neuroscience : the official journal of the Society for Neuroscience High 33172979
2021 FGF13A (nuclear isoform) interacts with ARID1B, a subunit of the Brahma-associated factor (BAF) chromatin remodeling complex, in hippocampal neural stem cells, and suppresses expression of neuronal differentiation-associated genes through chromatin modification, thereby maintaining neural stem cell self-renewal and suppressing neuronal differentiation during postnatal hippocampal neurogenesis. Fgf13 conditional knockout mice, co-immunoprecipitation (FGF13A-ARID1B), chromatin immunoprecipitation, hippocampal neurogenesis assays, RNA-seq Cell reports Medium 34010636
2024 FGF13 enhances TRPV1 channel function selectively (not TRPA1) in DRG neurons through its microtubule-stabilizing effect. FGF13 knockout reduces TRPV1-activated calcium influx and current density, impairing histamine-dependent and chronic dry-skin itch behaviors. Only FGF13 containing an intact tubulin-binding domain can rescue TRPV1 function and itch behavior in knockout mice. DRG-specific Fgf13 conditional KO mice, calcium imaging, whole-cell patch-clamp (DRG and HEK cells), rescue with wild-type vs tubulin-binding mutant FGF13, behavioral itch assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 38733310
2023 FGF13 deficiency in glomerular endothelial cells improves mitochondrial homeostasis in diabetic nephropathy through Parkin-dependent regulation of mitophagy promotion and apoptosis inhibition. The beneficial effects of Fgf13 deficiency on T2DN are abolished by endothelial-specific double deletion of Fgf13 and Prkn (Parkin), placing FGF13 upstream of Parkin in this pathway. Endothelial-specific Fgf13 KO and double Fgf13/Prkn KO mice, mitophagy assays, apoptosis assays, diabetic nephropathy model Diabetes Medium 36256844
2024 FGF13 interacts with microtubules in cardiomyocytes and increases microtubule stability during heart failure, impairing calcium signaling by reducing Cav1.2 sarcolemmal localization and Serca2α expression. FGF13 deficiency in heart failure restores calcium transients. Rescue with wild-type FGF13 but not a microtubule-binding-deficient FGF13 mutant recapitulates the calcium dysfunction, confirming that microtubule stabilization is the operative mechanism. Transaortic constriction heart failure model, Fgf13 KO, calcium imaging, patch-clamp, Western blotting, surface fractionation, rescue with wild-type vs tubulin-binding mutant FGF13 Biochemical pharmacology Medium 38821375
2021 FGF13 enhances resistance to platinum drugs (cisplatin) in cancer cells by regulating the expression and subcellular distribution of copper transporter hCTR1 and copper-transporting ATPase ATP7A, causing reduced platinum influx and promoting platinum sequestration/efflux. This effect requires the FGF13 microtubule-stabilizing domain; only FGF13 with an intact -SMIYRQQQ- tubulin-binding domain confers platinum resistance. FGF13 overexpression/knockdown in multiple cancer cell lines, platinum uptake assays, subcellular fractionation of hCTR1/ATP7A, domain mutant rescue experiments Cancer science Medium 34533854
2025 FGF13 is not secreted from neurons; it lacks a signal sequence and remains intracellular. Using rigorous controls, neither transfected FGF13 in heterologous cells nor endogenous FGF13 from cultured neurons was detected in conditioned medium. Proximity labeling proteomics confirmed FGF13 remains membrane-associated and inaccessible for interaction with extracellular protein domains. Conditioned medium collection from transfected cells and cultured neurons with positive/negative controls, proximity labeling proteomics (BioID/APEX), Western blotting JCI insight High 41289026
2025 FGF13 interacts with MCHT2 (a mitochondrial outer membrane protein) to anchor mitochondria in the neuronal cytoplasm. Under PD-related stress, decreased FGF13 induces release of damaged mitochondria that activate microglia and astrocytes, promoting neurodegeneration. Co-immunoprecipitation (FGF13-MCHT2), Fgf13 overexpression in PD mouse models, glia-neuron co-culture assays, mitochondria transfer assays Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40344619
2025 The FGF13/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception. PW164, an FGF13/Nav1.7 C-terminal tail domain PPI inhibitor, selectively suppresses Na+ currents sensitized by TRPV1 activation in hIPSC-derived sensory neurons and reduces mechanical and thermal hyperalgesia in mice. ZL192, a ligand stabilizing FGF13/Nav1.7 assembly, sensitizes Na+ currents and produces pronociceptive behavior. FGF13 silencing mimics PW164. In T2DN, the FGF13/Nav1.7 protein ratio is upregulated in donor DRG neurons. Small molecule PPI inhibitor/stabilizer, hIPSC-derived sensory neurons (patch-clamp), FGF13 siRNA knockdown in culture and in vivo, mouse behavioral assays, donor DRG protein quantification The Journal of clinical investigation High 40662354
2025 FGF13 regulates Caveolin-1 (Cav1) promoter activity and expression through the p38/MAPK pathway and nuclear translocation of p65, as well as by modulating PTRF binding to Cav1, thereby mediating cardiomyocyte senescence. FGF13 overexpression exacerbates and deficiency alleviates doxorubicin/D-galactose-induced premature cardiac aging. FGF13 regulates a Cav1-p53-p21 axis. AAV9-FGF13 overexpression, cardiac-specific Fgf13 KO mice, transcriptomics, luciferase reporter (Cav1 promoter), co-immunoprecipitation (PTRF-Cav1), p38/MAPK pathway inhibition Advanced science (Weinheim, Baden-Wurttemberg, Germany) Medium 40184605
2024 Cardiac fibrosis induced by pressure overload (TAC) is reduced by Fgf13 deletion. TGFβ-stimulated cardiac fibroblasts show increased collagen and α-SMA expression that is reduced by Fgf13 knockdown. The anti-fibrotic effect of FGF13 loss requires microtubule destabilization; wild-type FGF13 but not a microtubule-binding-deficient mutant rescues fibrosis markers. Fgf13 knockdown decreases ROCK protein expression via microtubule disruption. TAC mouse model, cardiac fibroblast culture, siRNA/overexpression with wild-type vs. tubulin-binding mutant FGF13, Western blotting for fibrosis markers and ROCK Acta biochimica et biophysica Sinica Medium 38818580
2020 FGF13 interacts with SHCBP1 in A549 lung cancer cells (confirmed by co-immunoprecipitation), and FGF13-SHCBP1 interaction cooperatively activates the AKT-GSK3α/β signaling pathway and inhibits p21/p27 to promote cell cycle G1-to-S transition and cell proliferation. Co-immunoprecipitation, Western blotting, cell cycle analysis by flow cytometry, CCK-8 proliferation assay Cancer biology & therapy Low 33064958
2026 FGF13 directly interacts with TUBB2A (a microtubule β-tubulin) as shown by co-immunoprecipitation. FGF13 methylation reduces this interaction. Overexpression of FGF13 improves microtubule stability and mitochondrial function in hippocampal neurons in an Alzheimer's disease mouse model; these protective effects are reversed by TUBB2A knockdown, placing FGF13 upstream of TUBB2A in microtubule stability maintenance. Co-immunoprecipitation (FGF13-TUBB2A), Methylation-Specific PCR, FGF13 overexpression in Aβ25-35 hippocampal injection AD model, TUBB2A knockdown epistasis, mitochondrial membrane potential/ROS assays FASEB journal : official publication of the Federation of American Societies for Experimental Biology Medium 41808420
2023 FHF2 (FGF13) is highly phosphorylated in native cardiac NaV1.5 channel complexes at nine phosphorylation sites identified by phosphoproteomics. FHF2 knockdown in adult cardiomyocytes increases late Na+ current and alters NaV channel inactivation rates; FHF2-VY isoform restores these effects. No specific phosphosite roles in NaV1.5 regulation could be identified (each phosphomutant rescued similarly to WT). Phosphoproteomic analysis of NaV channel complexes from mouse left ventricles, neonatal and adult cardiomyocyte knockdown/rescue models, patch-clamp electrophysiology bioRxiv : the preprint server for biologypreprint Medium 36778222

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Long non-coding RNA FGF13-AS1 inhibits glycolysis and stemness properties of breast cancer cells through FGF13-AS1/IGF2BPs/Myc feedback loop. Cancer letters 137 30771425
1997 Murine FGF-12 and FGF-13: expression in embryonic nervous system, connective tissue and heart. Mechanisms of development 109 9232594
2015 Disruption of Fgf13 causes synaptic excitatory-inhibitory imbalance and genetic epilepsy and febrile seizures plus. The Journal of neuroscience : the official journal of the Society for Neuroscience 76 26063919
1999 Fibroblast growth factor homologous factor 2 (FHF2): gene structure, expression and mapping to the Börjeson-Forssman-Lehmann syndrome region in Xq26 delineated by a duplication breakpoint in a BFLS-like patient. Human genetics 76 10071193
2017 FGF13 Selectively Regulates Heat Nociception by Interacting with Nav1.7. Neuron 73 28162808
2016 Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival. Proceedings of the National Academy of Sciences of the United States of America 66 27994142
2019 E2F1 Drives Breast Cancer Metastasis by Regulating the Target Gene FGF13 and Altering Cell Migration. Scientific reports 64 31341204
2016 Polarized localization of voltage-gated Na+ channels is regulated by concerted FGF13 and FGF14 action. Proceedings of the National Academy of Sciences of the United States of America 61 27044086
2017 Conditional knockout of Fgf13 in murine hearts increases arrhythmia susceptibility and reveals novel ion channel modulatory roles. Journal of molecular and cellular cardiology 46 28119060
2017 Lentivirus Mediating FGF13 Enhances Axon Regeneration after Spinal Cord Injury by Stabilizing Microtubule and Improving Mitochondrial Function. Journal of neurotrauma 45 28922963
2017 Inducible Fgf13 ablation enhances caveolae-mediated cardioprotection during cardiac pressure overload. Proceedings of the National Academy of Sciences of the United States of America 44 28461495
2013 Upregulated expression of FGF13/FHF2 mediates resistance to platinum drugs in cervical cancer cells. Scientific reports 44 24113164
2015 FGF13 regulates proliferation and differentiation of skeletal muscle by down-regulating Spry1. Cell proliferation 42 26230950
1999 Expression of chicken fibroblast growth factor homologous factor (FHF)-1 and of differentially spliced isoforms of FHF-2 during development and involvement of FHF-2 in chicken limb development. Development (Cambridge, England) 42 9847253
2016 Fhf2 gene deletion causes temperature-sensitive cardiac conduction failure. Nature communications 37 27701382
2020 FGF13 promotes metastasis of triple-negative breast cancer. International journal of cancer 34 31957002
2020 Missense variants in the N-terminal domain of the A isoform of FHF2/FGF13 cause an X-linked developmental and epileptic encephalopathy. American journal of human genetics 31 33245860
2017 C-terminal phosphorylation of NaV1.5 impairs FGF13-dependent regulation of channel inactivation. The Journal of biological chemistry 31 28882890
2019 Fibroblast growth factor homologous factor 2 (FGF-13) associates with Nav1.7 in DRG neurons and alters its current properties in an isoform-dependent manner. Neurobiology of pain (Cambridge, Mass.) 29 31223136
2016 FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons. Pflugers Archiv : European journal of physiology 29 27999940
2020 FGF13 Is a Novel Regulator of NF-κB and Potentiates Pathological Cardiac Hypertrophy. iScience 28 33089113
2016 FGF13 modulates the gating properties of the cardiac sodium channel Nav1.5 in an isoform-specific manner. Channels (Austin, Tex.) 28 27246624
2020 FGF13 interaction with SHCBP1 activates AKT-GSK3α/β signaling and promotes the proliferation of A549 cells. Cancer biology & therapy 24 33064958
2021 5'-UTR SNP of FGF13 causes translational defect and intellectual disability. eLife 22 34184986
1999 Pretreatment with intravenous FGF-13 reduces infarct volume and ameliorates neurological deficits following focal cerebral ischemia in rats. Brain research 22 9914447
2022 The Endo-α(1,4) Specific Fucoidanase Fhf2 From Formosa haliotis Releases Highly Sulfated Fucoidan Oligosaccharides. Frontiers in plant science 21 35185990
2019 MiR-10b suppresses the growth and metastasis of colorectal cancer cell by targeting FGF13. European review for medical and pharmacological sciences 20 30720165
2004 Bulge- and basal layer-specific expression of fibroblast growth factor-13 (FHF-2) in mouse skin. The Journal of investigative dermatology 20 15140207
2023 FGF13-Sensitive Alteration of Parkin Safeguards Mitochondrial Homeostasis in Endothelium of Diabetic Nephropathy. Diabetes 17 36256844
2021 Nuclear isoform of FGF13 regulates post-natal neurogenesis in the hippocampus through an epigenomic mechanism. Cell reports 15 34010636
2021 FGF13 enhances resistance to platinum drugs by regulating hCTR1 and ATP7A via a microtubule-stabilizing effect. Cancer science 14 34533854
2020 Ionic Mechanisms of Impulse Propagation Failure in the FHF2-Deficient Heart. Circulation research 14 32962518
2021 lncRNA LINC00963 downregulation regulates colorectal cancer tumorigenesis and progression via the miR‑10b/FGF13 axis. Molecular medicine reports 13 33495804
2020 FGF13 Is Required for Histamine-Induced Itch Sensation by Interaction with NaV1.7. The Journal of neuroscience : the official journal of the Society for Neuroscience 13 33172979
2024 FGF13 deficiency ameliorates calcium signaling abnormality in heart failure by regulating microtubule stability. Biochemical pharmacology 12 38821375
2024 Tumor-Derived Exosomal Circular RNA Pinin Induces FGF13 Expression to Promote Colorectal Cancer Progression through miR-1225-5p. Gut and liver 10 38384181
2023 Identification of FGF13 as a Potential Biomarker and Target for Diagnosis of Impaired Glucose Tolerance. International journal of molecular sciences 10 36675322
2021 Further evidence of affected females with a heterozygous variant in FGF13 causing X-linked developmental and epileptic encephalopathy 90. European journal of medical genetics 10 34871784
2025 Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism. eLife 9 39773461
2025 The FGF13-Caveolin-1 Axis: A Key Player in the Pathogenesis of Doxorubicin- and D-Galactose-Induced Premature Cardiac Aging. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 9 40184605
2018 Analysis of Parent-of-Origin Effects on the X Chromosome in Asian and European Orofacial Cleft Triads Identifies Associations with DMD, FGF13, EGFL6, and Additional Loci at Xp22.2. Frontiers in genetics 9 29520293
1998 Functional effects of FGF-13 on human lung fibroblasts, dermal microvascular endothelial cells, and aortic smooth muscle cells. Biochemical and biophysical research communications 9 9735346
2024 Inducible Fgf13 ablation alleviates cardiac fibrosis via regulation of microtubule stability. Acta biochimica et biophysica Sinica 8 38818580
2025 Ceramide-induced FGF13 impairs systemic metabolic health. Cell metabolism 7 40169001
2025 Neuronal FGF13 Inhibits Mitochondria-Derived Damage Signals to Prevent Neuroinflammation and Neurodegeneration in a Mouse Model of Parkinson's Disease. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 7 40344619
2025 FGF13 prevents age-related hearing loss by protecting spiral ganglion neurons and ribbon synapses from injury. Cell death discovery 6 40617800
2025 Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models. The Journal of clinical investigation 6 40662354
2016 Is FGF13 a major contributor to genetic epilepsy with febrile seizures plus? Epilepsy research 6 27810516
2021 MiR-421 regulates goat intramuscular preadipocytes differentiation via targeting FGF13. Animal biotechnology 5 33914665
2024 FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 4 38733310
2021 FGF10 and FGF13 genetic variation and tooth-size discrepancies. The Angle orthodontist 4 33492380
2019 Polymorphisms in FGF3, FGF10, and FGF13 May Contribute to the Presence of Temporomandibular Disorders in Patients Who Required Orthognathic Surgery. The Journal of craniofacial surgery 4 31574782
2025 FGF13 regulates cardiomyocyte impulse propagation via Cx43 trafficking independent of voltage-gated sodium channels. bioRxiv : the preprint server for biology 3 40777326
2025 The NaV1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding. The Journal of clinical investigation 3 40794434
2022 FGF13 suppresses acute myeloid leukemia by regulating bone marrow niches. Frontiers of medicine 3 36053411
2021 Expression and cellular distribution of FGF13 in cortical tubers of the tuberous sclerosis complex. Neuroscience letters 3 33582188
2025 The Na V 1.5 auxiliary subunit FGF13 modulates channels by regulating membrane cholesterol independent of channel binding. bioRxiv : the preprint server for biology 1 40166257
2025 FGF13 Regulates VGSC-Independent Cardiomyocyte Impulse Propagation via Cx43 Trafficking. Circulation research 1 41200819
2024 Decreased Left Atrial Cardiomyocyte FGF13 Expression Increases Vulnerability to Postoperative Atrial Fibrillation in Humans. bioRxiv : the preprint server for biology 1 38352455
2024 Interneuron FGF13 regulates seizure susceptibility via a sodium channel-independent mechanism. bioRxiv : the preprint server for biology 1 38659789
2002 FHF-2 in the turkey (Meleagris gallopavo). Animal biotechnology 1 12517074
2026 A bioinspired anisotropic anti-inflammatory scaffold enhances spinal nerve regeneration and neural circuit reconstruction via FGF13/Ca2+/CaMK2A/CREB pathway. Materials today. Bio 0 41737465
2026 Hypermethylation of FGF13 Reduces Microtubule Stability via Interaction With TUBB2A to Promote Mitochondrial Dysfunction in Alzheimer's Disease. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41808420
2026 LncRNA FGF13-AS1 predicts delayed fracture healing and promotes osteoporotic fracture healing by regulating miR-128-3p/CBFB-mediated osteogenesis and osteoclast activity. Bone 0 42025821
2025 FGF13 is not secreted from mouse neurons. JCI insight 0 41289026
2025 FGF13 is not secreted from neurons. bioRxiv : the preprint server for biology 0 41292799
2024 miR-421-mediated suppression of FGF13 as a novel mechanism ameliorates cardiac hypertrophy by inhibiting endoplasmic reticulum stress. European journal of pharmacology 0 39486770
2023 FHF2 phosphorylation and regulation of native myocardial Na V 1.5 channels. bioRxiv : the preprint server for biology 0 36778222

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